Cancers of the breast are one of the leading causes of death among women, with the cumulative lifetime risk of a woman developing breast cancer estimated to be 1 in 9. Consequently, understanding the origins of these malignancies as well as models for the identification of new diagnostic and therapeutic modalities is of significant interest to health care professionals.
Most women that die from breast cancer succumb not to the original primary disease, which is usually amenable to various therapies, but rather from metastatic spread of the breast cancer to distant sites. This fact underscores the need to develop either novel anticancer agents or more aggressive forms of therapy directed specifically against the metastatic breast tumor cell. Requisite to the development of new treatment modalities is a fundamental, thorough understanding of the regulatory processes inherent to the growth of both the primary and metastatic breast cancer cell and tumor. This process has been severely hampered by the lack of appropriate and clinically relevant modeling systems.
Recent experimental studies have suggested that the step of intravasation is a rate limiting though poorly understood step of the metastatic process (Kim et al., Cell, 94: 353–362, 1998; Quigley et al., Cell, 94: 281–284, 1998.). Inflammatory breast carcinoma is a representative cancer in humans which exhibits an exaggerated degree of intravasation in situ manifested by florid invasion of lymphatic and vascular capillaries. Inflammatory breast cancer is one of the most aggressive types of human breast cancer (Levine et al., J. Natl. Cancer Inst., 74: 291–297, 1985.). Clinically patients present with an inflamed tender breast with the so called erysipelas edge and/or peau d'orange. Pathologically there is extensive lymphovascular invasion by tumor emboli which involve the superficial dermal plexus of vessels in the papillary dermis and high reticular dermis. Inflammatory carcinomas tend to exhibit axillary nodal metastases, a high incidence of local and systemic recurrence and distal metastases. Inflammatory carcinomas can occur in either primary or secondary forms, the latter term referring to a non-inflammatory primary carcinoma which recurs as an inflammatory carcinoma. Locally advanced non-inflammatory primary cancers which are successfully treated with neo-adjuvant chemotherapy often show evidence microscopically of residual carcinoma presently almost exclusively in lymphovascular channels.
In view of the above, what is needed in the art are novel models for the evaluation, diagnosis and generation of therapies for metastatic cancers, in particular inflammatory breast cancer. In this context, optimal models are those which provide insight into metastatic processes such as intravasation, as these models have a wide application both in the diagnosis of cancer, as well as the generation of prophylactic and therapeutic treatments for cancer.